Common Neuropsychiatric Drug Interactions in Egypt That Require Clinical Interventions: A Retrospective Study in Delta Region

With the increasing burden of patients with multiple disease states and drug combinations, pharmacotherapy has become more complex [1]. The polytherapeutic regimens increase the risk of drug-drug interaction (DDI) to a great extent. DDIs occur when the effect of one drug is altered by the concurrent administration of another medication. Drug interactions are not only attributed to interactions to other drugs but also natural supplements and food. Drug interactions can occur either by pharmacokinetic or pharmacodynamics mechanisms [2]. Pharmacokinetic drug interactions occur when the concurrently administered drug has a potential to alter one of the pharmacokinetic parameters; absorption, distribution, metabolism and excretion of the other drug [3]. On the other hand, pharmacodynamic drug interactions occur if concurrently administered drugs have agonist or antagonist effects for either therapeutic efficacy or adverse effects [3]. Outcomes from DDIs can lead to severe adverse drug reactions (ADRs) resulting in hospitalizations and life-threatening conditions. About 6-30% of all ADRs are attributed to DDIs [4]. Furthermore, ADR caused by DDIs accounts for about 2.8% of hospital admission every year in USA [5]. In addition, DDIs may result in diminished or increased therapeutic effect or adverse effects of one or both medications.

Recent treatment guidelines of neuropsychiatric disorders usually involve many therapeutic regimens [6]. The therapeutic classes for neurological disorders include dopamine agonists, catechol-o-methyltransferase “COMT” inhibitors and anticholinergic drugs for Parkinson’s Disease and benzodiazepines and carbamazepine for epilepsy. In addition, the study involved some of the most common anti-depressants such as tricyclic anti-depressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs) and antipsychotics for bipolar disorders [6,7]. It is noteworthy that multiple drug administration increases the potential for significant drug interactions in clinical practice affecting both therapeutic efficacy and adverse drug events of medications [7,8]. However, there are no previous reports about the incidence of potential drug interactions with patients treated with medications for neuropsychiatric disorders in Egypt. Incidence and pattern of these DDIs in Egypt are not well-documented and little information is available. For this reason, this study aimed to identify the potential drug interactions with neuropsychiatric drugs for outpatients in Egypt giving insights about incidence, mechanisms, outcomes and major interacting therapeutic classes.

An observational retrospective study was performed on Egyptian outpatients who got their medications dispensed from Egyptian community pharmacies in Delta region of Egypt. The Delta region includes five Governorates “Kafrelsheikh, Menoufia, Gharbia, Damnhour, Dakahlia”. Patients aged 18 years or older were included in the study. The study was approved by the Research Ethics Committee of Kafrelsheikh University according to Helsinki declaration. All participants gave their consent forms. Prescriptions were collected over a 12 months-period from January 1, 2020, till January 1, 2021, to ensure that drugs commonly prescribed in all environmental seasons are included. Neuropsychiatric and neurological disorders that were included in this study were epilepsy, Parkinson’s Disease, Alzheimer’s Disease, depression. Pharmacological classes for neurologic disorders included Anti-parkinsonian medications (dopamine agonist, catechol-o-methyltransferase “COMT” inhibitors and anticholinergic) and antiepileptic drugs (benzodiazepines, valproic acid, phenytoin, carbamazepine, gabapentin, pregabalin and piracetam). Pharmacological classes for psychiatric disorders that were included in the study include TCAs (amitriptyline, clomipramine), SSRI (citalopram, dapoxetine, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline), SNRIs (duloxetine) and hypericum perforatum for depression and anti-psychotic drugs (olanzapine, clozapine, quetiapine, chlorpromazine, and sulpiride).

Lexicomp Analysis: All prescriptions contained neuropsychiatric drugs were analyzed for potential drug-drug interactions using lexicomp® (Lexicomp, Inc., Ohio, USA) DDI database. In Lexicomp, a potential DDI can take a five-risk rating category from A, B, C, D and X which reflects both the level of urgency and the actions necessary to overcome the interaction. While category A has no reported drug interactions, category B and C are where there is a potential less serious DDI that does not require any action or to monitor therapy; respectively. Potential DDIs included in this report are either “D” and “X”-risk ratings since they include serious DDI that require modification of drug therapy or avoiding drug combinations; respectively. Data were analyzed for incidence, major interacting therapeutic classes, outcomes and mechanisms of actions.

Statistical analysis: Descriptive statistics were used to calculate the incidence of a potential dug interaction. All the statistical analysis was carried out with Statistical Package for Social Sciences (SPSS, IBM corporation version 16.0) considering P < 0.01 as statistically significant.

Exactly 4341 prescriptions were included in the study and analyzed. Participants demographics were presented in the (Table 1).

Table 1:Basic Patients Demographic data.

As revealed from (Figure 1), 623 potential drug interactions were identified. The overall incidence for potential drugdrug interactions was 14%. Only 86 potential interactions with neuropsychiatric drugs were reported (2% of the overall prescription). About 16 interactions for every one thousand prescriptions showed category D interactions. On the other hand, about 4 interactions for every one thousand prescriptions showed category X interactions.

(Table 2) shows the list of potential DDI with neuropsychiatric drugs “risk rating D or X”. As shown from the table, the outcomes and mechanisms of drug interactions varied according to the nature of the drug.

Table 2:List of potential drug interactions with neuropsychiatric drugs.

Pk: Pharmacokinetics, PD: Pharmacodynamics, COMT: Catechol-o-methyl-transferase, CYP: Cytochrome, TCA: Tricyclic antidepressants, SSRI: selective serotonin reuptake inhibitors, SNRI: serotonin norepinephrine reuptake inhibitors Benzodiaz: Benzodiazepine, Carbamaz: Carbamazepine, NSAIDs: Non-steroidal anti-inflammatory drugs.

In addition, (Table 3) revealed the different mechanisms of neuropsychiatric drug interactions. Additive pharmacodynamic effects were the main mechanisms for interactions with antipsychotics and antidepressants. While metabolic inhibitions or induction of CYP450 were the main mechanisms for interactions with antiepileptic drugs.

Table 3:Mechanisms of neuropsychiatric drug interactions.

The incidence of drug interactions with neuropsychiatric according to pharmacological classes was shown in (Figure 2). The three major therapeutic classes representing 85% of potential interaction were antidepressants, antiepileptic, and antipsychotic drugs 36%, 31%, and 18%, respectively [7-9]. Similarly, the three major pharmacological classes representing 50% of potential interactions were SSRI, antipsychotics, and carbamazepine 20%, 18% and 12%, respectively [8,10-12].

(Tables 4) showed major therapeutic classes of drugs that interact with neuropsychiatric drug. The three major therapeutic classes “represent 51% of potential interaction” were antipsychotics, muscle relaxants, and proton pump inhibitors 23%, 16%, and 12%, respectively. Consequently, these classes required more attention when prescribed with neuropsychiatric drugs to avoid any probable drug interactions.

Table 4:Major therapeutic classes that interact with neuropsychiatric drug.

Pearson correlation coefficient revealed that there was no significant correlation between reported risk factors “liver disorders, renal disorders, heart disorders, diabetes” and incidence and/or severity of drug interactions with neuropsychiatric diseases.

Most neuropsychiatric patients take many drugs meaning many drugs per prescription in recent guidelines. This polypharmacy increases the likelihood of DDIs [7,13]. To our knowledge, this study was the first one that evaluates neuropsychiatric DDIs in Egyptian outpatients´ prescriptions. This study showed that that Incidence of potential neuropsychiatric DDIs in Egypt was 14% of neuropsychiatric DDIs. This study explored the importance of the preventive program to avoid potential medication errors in clinical practice and to avoid any hazardous effects of these interactions on Egyptian patients.

The major interacting classes were antidepressants, antiepileptic, and antipsychotic drugs. This shows the importance of giving more attention to these therapeutic classes in clinical practice. These classes require drug interaction evaluation with other concurrent drugs before dispensing their prescriptions. In pharmacy practice, the significant role of the pharmacist in checking prescription for any possible interaction with these therapeutic classes should be emphasized to prevent possible medication errors and avoiding any expected harmful outcomes [14].

As reported from this study, awareness of mechanisms of DDIs is very crucial to expect possible similar interactions with similar drugs in the therapeutic classes and whether the interactions are drug specific or class specific. In addition, being alert full of potential DDIs help suggest the possible alternative to avoid these interactions. This study showed that pharmacodynamic effects on dopamine and serotonin receptors were the main mechanisms for interactions with antipsychotics and antidepressants. While metabolic alterations of CYP450 mainly CYP3A4 were the main mechanisms for interactions with antiepileptic drugs.

Previous studies found similar results considering the association between patient characteristics and the prediction DDI. Abolhassani et al. studied 17,742 adult patients discharged between 2009 and 2015 from a department of internal medicine at Swiss hospital [15]. They found that age, number of comorbidities and a higher Charlson Comorbidity Index independently associated with polypharmacy. Similarly, Pérez et al. studied 38,299 patients in Ireland between 2012 and 2015 and found that age and multimorbidity were associated with a higher risk of DDI [15]. Furthermore, they found that hospital admissions themselves were independently associated with a higher risk of DDIs.

Limitations of this study include that these studies did not investigate psychiatric inpatients. To the best of our knowledge, there is currently no evidence comparable in scale and scope investigating the prediction of polypharmacy and the risk of DDI in hospital psychiatric units. Predicting other outcomes in hospitalized patients has often been found to be more complex in psychiatry than in other medical disciplines [16-18]. There are many reasons contributing to the difficulty of studying DDIs in psychiatric inpatients including less distinct diagnostic concepts, less standardization of care and a broader spectrum of acceptable therapeutic regimes [19-24]. Further studies are required to evaluate the DDIs in neuropsychiatric inpatients. In addition, prescription for pediatrics and more regions from different governorates of Egypt should be included in further studies. Also, natural supplements and herbal products including beverages and juices like green tea and grapefruit juices should be considered in further drug interactions evaluations [25-26].

Egyptian outpatients taking neuropsychiatric drugs are at a high risk of hazardous DDIs as revealed from the reported incidence from prescription. This emphasizes the need for the evaluation of potential DDIs during prescription writing to protect patients from harmful outcomes of drug interactions. In addition, providing DDIrelated information to the prescribers and using drug interaction software programs to the dispensing pharmacist can play a vital role in minimizing the incidence rate of DDIs. The preventive program monitoring for interactions outcome and increasing awareness of potential drug interaction are recommended in clinical practice in Egypt.

Khaled Abdelkawy conceived of the research and study design and revised the manuscript. All authors contributed to data collection and statistical analysis. Mohamed Abdelgaied wrote the first draft of the manuscript. Michael G Zaki and Khaled Abdelkawy revised the manuscript. All authors read and approved the final manuscript.

The data that support the findings of this study are available upon request from the corresponding author.

None.

No Conflict of Interest.

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